Antibiotic resistance is on the rise globally. This is due in part to transferable resistance genes and also to the selective pressure associated with the increased use of antibiotics. In addition to the widespread use in hospitals, there is often broad scale antibiotic prophylactic use in animal husbandry especially where large numbers of animals are kept in close quarters where infections can easily spread. In addition, antibiotics are often used as growth promoters, especially in poultry and pig farming. There is speculation that the wide use of antibiotics in agriculture has contributed to the transfer of antibiotic resistant microorganisms to humans and the increased identification of transferable resistance genes. Thus there is a real need for the development of novel antibiotics that can be used to treat resistant bacterial infections.
Despite being discovered over 50 years ago, the streptogramin antibiotics have only recently seen significant clinical use [1]. The semisynthetic streptogramin formulation Synercid was approved by the FDA in 1999 for the treatment of serious life-threatening infections caused by antibiotic resistant gram-positive bacterial pathogens such as vancomycin-resistant enterococci [2,3]. Streptogramins are produced by various soil bacteria of the genus Streptomyces and consist of two chemically distinct components: type A and type B. The type A streptogramins are cyclic hybrid peptide-polyketide macrolactones [4]. Type B streptogramins are cyclic depsipeptides consisting of 6–7 amino acids. These peptides are cyclized via an ester bond between the C-terminatl carboxyl group and the secondary hydroxyl group of an invariant Thr residue at position 2. The mode of action of both type A and type B streptogramins is through inhibition of translation by binding to bacterial ribosomes [5]. The available evidence indicates that binding of the type A component facilitates binding of the type B streptogramins, a phenomenon that results in synergy of action and bacterial cell death [6]. Recent X-ray structure analysis of the 50S ribosomal subunit in complex with these antibiotics has revealed that type B streptogramins block the peptide exit tunnel while the type A streptogramins bind to the peptidyl transfer center [7].
The only clinically approved streptogramin in North America, Syncercid, is a combination of dalfopristin (type A), and quinupristin (type B). Despite the relatively recent clinical introduction of this antibiotic, resistance to each component is well documented (reviewed in [8]). This may be the result of the fact that streptogramins have long been used in agriculture as animal growth promotion agents. In fact, studies have shown that commercial meat products can be contaminated with streptogram-resistant organisms [9–11].
Resistance to the type B streptogramins can result from active efflux (Msr pumps), alteration of the target ribosome by methylation of the 23S rRNA (Erm methyl-transferases), and by the inactivating enzyme Vgb. Vgb was originally found in streptogramin-resistant Staphylococcus aureus [12] but has now been identified in other gram-positive bacteria such as Enterococcus faecium [13]. The enzyme was thought to be a hydrolse but has now been determined to be a lyase that linearizes the cyclic depsipeptide through a novel elimination reaction [14]. This reaction results in cleavage of the ester bond between the C terminus of the peptide and a secondary hydroxyl group derived from the Thr residue found at position 2 of the type B streptogramin peptide.
As the incidence of antibiotic resistance increases, there is a growing need for novel antibiotic compounds that can be used to treat infections.